Emrelis
(telisotuzumab vedotin-tllv)Dosage & Administration
For intravenous infusion only.
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Emrelis Prescribing Information
EMRELIS is indicated for the treatment of adult patients with locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression [≥50% of tumor cells with strong (3+) staining], as determined by an FDA-approved test [see Dosage and Administration ( 2.1)], who have received a prior systemic therapy.
This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR) [see Clinical Studies ( 14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
2.1 Patient Selection
Select patients for treatment with EMRELIS based on the presence of high c-Met protein overexpression [≥50% of tumor cells with strong (3+) staining] in patients with non-squamous NSCLC [see Indications and Usage ( 1) and Clinical Studies ( 14)].
Information on FDA-approved tests for the detection of high c-Met protein overexpression is available at: http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dosage
The recommended dosage of EMRELIS is 1.9 mg/kg (up to a maximum of 190 mg for patients greater than or equal to 100 kg) administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.
2.3 Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions are provided in Table 1.
| Dose Reduction | Recommended Dosage |
| First | 1.6 mg/kg every 2 weeks |
| Second | 1.3 mg/kg every 2 weeks |
| Third | 1 mg/kg every 2 weeks |
| Permanently discontinue EMRELIS in patients who are unable to tolerate 1 mg/kg. | |
The recommended dosage modifications of EMRELIS for adverse reactions are provided in Table 2.
| Adverse Reaction | Severitya | Dosage Modification |
| Peripheral Neuropathy [see Warnings and Precautions ( 5.1)] | Grade 2 or 3 |
|
| Grade 4 | Permanently discontinue EMRELIS. | |
| Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions ( 5.2)] | Grade 1 |
|
| Grade ≥2 | Permanently discontinue EMRELIS. | |
| Keratitis [see Warnings and Precautions ( 5.3)] | Grade 2 |
|
| Grade 3 or 4 |
| |
| Infusion-Related Reactions (IRR) [see Warnings and Precautions ( 5.4)] | Grade 1-3 |
|
| Grade 4 |
| |
| Peripheral Edema [see Adverse Reactions ( 6.1)] | Grade ≥2 | First occurrence
|
| Other Adverse Reactions [see Adverse Reactions ( 6.1)] | Grade 3 | First occurrence
|
| Grade 4 |
| |
| aAdverse reactions were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 | ||
2.4 Recommended Premedications for Patients Who Experience Infusion-Related Reactions
Table 3 contains the recommended premedications for patients who experience infusion-related reactions to EMRELIS, for subsequent infusions.
| Medication Class | Examples or equivalent | Dose | Route of Administration | Dosing Window Prior to EMRELIS Administration |
| H1 Antihistamine | Diphenhydramine | 25 to 50 mg | Intravenously or orally | Administer 30-60 minutes prior to each infusion |
| H2 Antihistamine | Famotidine | 20 mg | Intravenously or orally | Administer 30-60 minutes prior to each infusion |
| Antipyretic | Acetaminophen | 650 to 1,000 mg | Intravenously or orally | Administer 30-60 minutes prior to each infusion |
| Glucocorticoid | Methylprednisolone | 125 mg or equivalent | Intravenously | Administer 30-60 minutes prior to each infusion |
2.5 Preparation and Administration
EMRELIS contains a hazardous component. Follow applicable special handling and disposal procedures in accordance with local requirements.1
Reconstitute and further dilute EMRELIS prior to intravenous infusion.
Reconstitution of Lyophilized EMRELIS
Before reconstitution, allow the vial to reach room temperature after removal of the vial from storage condition.
- Calculate the recommended dose based on the patient’s weight to determine the number of vials needed. For patients weighing greater than or equal to 100 kg, use 190 mg dose [see Dosage and Administration ( 2.2)]. More than one vial may be needed to achieve the calculated dose.
- Using a sterile syringe, slowly inject Sterile Water for Injection, using the volume provided in Table 4, into the EMRELIS vial containing the lyophilized powder, which has a whole or fragmented cake-like appearance. The reconstituted solution has a concentration of 20 mg/mL EMRELIS.
| Dose Vial | Volume of Sterile Water for Injection required for reconstitution |
| 20 mg vial | 1.1 mL |
| 100 mg vial | 5.2 mL |
- Swirl the vial gently until completely dissolved. Do not shake.
- Inspect the reconstituted solution for particulate matter and discoloration. The solution should appear clear to slightly opalescent and colorless to slightly yellow. Discard the vial if the reconstituted solution is discolored, is cloudy, or contains visible particulates.
- Use reconstituted EMRELIS immediately. If not used immediately, store the reconstituted EMRELIS vials in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours from the time of reconstitution. Do not freeze.
- Each vial of EMRELIS is intended for one-time use only. Discard any unused drug remaining in the vial.
Dilution in Infusion Bag
- Calculate the required dose volume (mL) of reconstituted EMRELIS solution based on the prescribed dose.
- Withdraw the calculated dose volume (mL) of reconstituted solution from the EMRELIS vial using a sterile syringe. Discard any unused portion remaining in the vial(s).
- Inject the calculated amount of reconstituted solution into 0.9% Sodium Chloride Injection infusion bag so that the final EMRELIS concentration is between 1 mg/mL and 10 mg/mL. Use only 0.9% Sodium Chloride Injection.
- Gently invert the infusion bag to thoroughly mix the solution. Do not shake.
- After preparing the dose for infusion, visually inspect the bag content for particulates and discard if present.
- If not used immediately, the diluted solution can be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours and an additional 4 hours at room temperature at 9°C to 30°C (48°F to 86°F) until the end of administration. Do not freeze.
Method of Administration
If the prepared infusion solution was stored refrigerated at 2°C to 8°C (36°F to 46°F), allow the solution to reach room temperature prior to administration.
- Administer by intravenous infusion over 30 minutes using a dedicated infusion line with a 0.20 or 0.22 micron in-line filter made of polyether sulfone (PES), polyvinylidene fluoride (PVDF), or Polyamide (PA).
- Do not mix EMRELIS with other drugs or administer other drugs through the same intravenous line.
For injection: 20 mg or 100 mg of telisotuzumab vedotin-tllv as a white to off-white, lyophilized powder in a single-dose vial for reconstitution and further dilution.
8.1 Pregnancy
Risk Summary
Based on the mechanism of action and findings in animals, EMRELIS can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)]. There are no available human data on EMRELIS use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of the small molecule component of EMRELIS, MMAE, to pregnant rats during organogenesis resulted in embryo-fetal mortality and structural abnormalities at exposures similar to the clinical exposure at the recommended dose [see Data]. Advise patients of the potential risks to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
No embryo-fetal development studies in animals have been performed with telisotuzumab vedotin-tllv. In an embryo-fetal development study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of EMRELIS, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, agnathia, malrotated limbs, and gastroschisis compared to controls at a dose of 0.2 mg/kg (approximately 2 times the human area under the curve [AUC] at the recommended dose).
8.2 Lactation
Risk Summary
There are no data on the presence of telisotuzumab vedotin-tllv or MMAE in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with EMRELIS and for 1 month after the last dose.
8.3 Females and Males of Reproductive Potential
EMRELIS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating EMRELIS treatment.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with EMRELIS and for 2 months after the last dose.
Males
Based on genotoxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment with EMRELIS and for 4 months after the last dose.
Infertility
Females
Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), EMRELIS may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology ( 13.1)].
Males
Based on findings from animal studies, EMRELIS may impair male fertility. The reversibility of this effect is unknown [see Nonclinical Toxicology ( 13.1)].
8.4 Pediatric Use
Safety and effectiveness of EMRELIS have not been established in pediatric patients.
8.5 Geriatric Use
Of the 168 patients with previously treated EGFR wild-type non-squamous NSCLC with c-Met protein overexpression treated with EMRELIS in LUMINOSITY, 50% were ≥65 years of age and 12% were ≥75 years of age. No overall differences in safety or effectiveness were observed between older and younger patients.
8.6 Hepatic Impairment
Avoid use of EMRELIS in patients with moderate or severe hepatic impairment (total bilirubin >1.5 x ULN and any AST).
Patients with moderate or severe hepatic impairment are likely to have increased exposure to MMAE, which may increase the risk of adverse reactions. EMRELIS has not been studied in patients with moderate or severe hepatic impairment.
No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >ULN and ≤1.5 x ULN and any AST) [see Clinical Pharmacology ( 12.3)].
None.
5.1 Peripheral Neuropathy
EMRELIS can cause peripheral neuropathy, including peripheral sensory neuropathy and peripheral motor neuropathy.
In the safety population [see Adverse Reactions ( 6.1)], peripheral neuropathy occurred in 51% of patients treated with EMRELIS, including Grade 3 in 11%. These adverse reactions included peripheral sensory neuropathy in 45% of patients and peripheral motor neuropathy in 9%. The median time to onset of peripheral neuropathy was 105 days (range: 1 to 472 days). Peripheral neuropathy led to permanent discontinuation of EMRELIS in 13% of patients. The median time to onset of peripheral neuropathy leading to treatment discontinuation was 249 days (range: 57 to 519 days). Of the 7 patients with motor neuropathy ongoing as of their last dose of EMRELIS, 6 had persistent Grade 1 or 2 symptoms 30 days after their last dose.
Monitor patients for signs and symptoms of new or worsening peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, a burning sensation, neuropathic pain, or muscle weakness. Withhold, reduce the dose or permanently discontinue EMRELIS based on severity [see Dosage and Administration ( 2.3)].
5.2 Interstitial Lung Disease/Pneumonitis
EMRELIS can cause severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis.
In the safety population [see Adverse Reactions ( 6.1)], ILD/pneumonitis occurred in 10% of patients treated with EMRELIS, including Grade 3 in 3% and Grade 4 in 0.6%. There were 3 fatal cases of ILD/pneumonitis in patients who received EMRELIS. The median time to onset of ILD/pneumonitis was 48 days (range: 23 to 85 days). ILD/pneumonitis led to permanent discontinuation of EMRELIS in 7% of patients. The median time to onset of ILD/pneumonitis leading to treatment discontinuation was 46 days (range: 23 to 85 days).
Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD/pneumonitis. Withhold or permanently discontinue EMRELIS based on severity [see Dosage and Administration ( 2.3)].
5.3 Ocular Surface Disorders
EMRELIS can cause ocular surface disorders including blurred vision, visual impairment, keratitis, and dry eye.
In the safety population [see Adverse Reactions ( 6.1)], ocular surface disorders occurred in 25% of patients treated with EMRELIS. The most common ocular surface disorders were blurred vision (15%), keratitis (11%), and dry eye (5%). Grade 3 ocular surface disorders occurred in 1.2% of patients [blurred vision (1.2%), and keratitis (0.6%)]. The median time to onset of ocular surface disorders was 47 days (range: 1 to 319 days).
Monitor patients for ocular surface disorders during treatment with EMRELIS. Withhold EMRELIS and refer patients to an eye care professional for an ophthalmic examination and treatment for patients who develop Grade ≥2 ocular toxicity. Withhold or permanently discontinue EMRELIS based on severity [see Dosage and Administration ( 2.3)].
5.4 Infusion-Related Reactions
EMRELIS can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, chills, nausea, chest discomfort, and hypotension. The median time to onset of IRR was 28 days (range: 1 to 43 days).
In the safety population, [see Adverse Reactions ( 6.1)], IRR occurred in 3% of patients treated with EMRELIS including Grade 3 in 1.2% and Grade 4 in 0.6%. IRR led to permanent discontinuation of EMRELIS in 0.6% of patients.
Monitor patients for signs and symptoms of infusion reactions during EMRELIS infusion. Withhold, reduce the rate of infusion, or permanently discontinue EMRELIS based on severity [see Dosage and Administration ( 2.3)]. For patients who experience IRR, administer premedications prior to subsequent infusions.
5.5 Embryo-Fetal Toxicity
Based on the mechanism of action and findings in animals, EMRELIS can cause fetal harm when administered to a pregnant woman. The small molecule component of EMRELIS, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures similar to those occurring clinically at the recommended dose.
Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with EMRELIS and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with EMRELIS and for 4 months after the last dose [see Use in Specific Populations ( 8.1, 8.3) and Clinical Pharmacology ( 12.1)].